The objective of this proposal is to develop Nanogels for the targeted systemic delivery of siRNA to activated microvascular endothelial cells (MVEC) to attenuate tumor-associated angiogenesis and subsequent tumor growth. We posit that 1) the affinity of siRNA-loaded Nanogels for the surface of activated MVEC can be selectively increased in the presence of blood plasma and 2) this will increase the anti-tumor efficacy of Nanogel-delivered siRNA. A vascular cell-restricted protein required for angiogenesis, p73RhoGAP, will be targeted by siRNA. The hypotheses will be tested with mouse skin MVEC and cells from the mouse vascular compartment in vitro and a mouse model of melanoma in vivo. First, targeting ligand modifications that maximize binding selectivity of Nanogel-siRNA for the surface of activated MVEC will be established. Second, the efficacy of targeted Nanogel-siRNA against MVEC proliferation and migration will be determined in vitro. Third, the efficacy of targeted Nanogel-siRNA will be determined in vivo by measuring biodistribution, anti- vascular, and anti-tumor activity. If successful this work will lead to more efficacious anti-angiogenesis treatments of cancer. The recruitment of blood vessels from existing vasculature (angiogenesis) is a critical factor in the growth and spread (metastasis) of most cancers [Folkman et al., 2001]. Considering that metastasis is responsible for the majority of cancer-related deaths [Bogenrieder and Herlyn, 2003], blocking angiogenesis has much potential in the treatment of cancer. Thus, the long term goal of these studies is to develop more effective targeted drug delivery nanocarriers for the anti-angiogenesis treatment of cancer. [unreadable] [unreadable] [unreadable]